Glioblastoma is highly resistant to radiation therapy. The underlying molecular mechanism is not completely understood. The DNA damage response (DDR) pathway plays a crucial role in radioresistance of glioablastoma cells. Growing evidence has demonstrated that radiation induces alterations in microRNA (miR) profiles. However, how radiation induces specific miRs and how they might regulate the DDR remain elusive. In our study, we found that radiation induced c-jun transcription of miR-221 and miR-222. miR-221 and miR- 222 modulated DNA-PKcs expression to affect DNA damage repair by activating Akt independent of PTEN status. Knocking down of miR-221/222 significantly increased radiosensitivity of glioblastoma cells. Inhibition of Akt by RNAi or LY294002 treatment may overcome miR-221/222 induced radioresistance. Notably, combined anti-miR-221/222 and radiotherapy has remarkably inhibited tumor growth compared with anti-miR-221/222 or radiotherapy alone in a subcutaneous mouse model. Our results suggest that radio-induced c-jun promotes transcription of miR-221/222, which mediates DNA damage repair of glioblastoma cells independent of PTEN. These data indicate for the first time that miR-221/222 play an important role in mediating radio-induced DNA damage repair and that miR-221/222 could serve as potential therapeutic targets for increasing radiosensitivity of glioblastoma cells.
BackgroundGlucocorticoid released by stressful stimuli elicits various stress responses. Acute treatment with a single dose of corticosterone (CORT; predominant glucocorticoid of rats) alone has previously been shown to trigger anxiety behavior and robust dendritic hypertrophy of neurons in the basolateral amygdala (BLA). Neurons in the medial prefrontal cortex (mPFC) are also known to be highly sensitive to stress and regulate anxiety-like behaviors. Nevertheless, we know less about acute CORT-induced structural changes of other brain regions and their behavioral outcomes. In addition, the temporal profile of acute CORT effects remains to be examined. The current study investigates time course changes of dendritic architectures in the stress vulnerable brain areas, the BLA and mPFC, and their behavioral consequences after acute treatment with a single dose of CORT.ResultsAcute CORT treatment produced delayed onset of dendritic remodeling in the opposite direction in the BLA and mPFC with different time courses. Acute CORT induced dendritic hypertrophy of BLA spiny neurons, which was paralleled by heightened anxiety, both peaked 12聽days after the treatment. Meanwhile, CORT-induced dendritic atrophy of mPFC pyramidal neurons peaked on day 6, concomitantly with impaired working memory. Both changed dendritic morphologies and altered behavioral outcomes were fully recovered.ConclusionOur results suggest that stress-induced heightened anxiety appears to be a functional consequence of dendritic remodeling of BLA neurons but not that of mPFC. Instead, stress-induced dendritic atrophy of mPFC neurons is relevant to working memory deficit. Therefore, structural changes in the BLA and the mPFC might be specifically associated with distinct behavioral symptoms observed in stress-related mental disorders. Remarkably, stress-induced dendritic remodeling in the BLA as well as mPFC is readily reversible. The related behavioral outcomes also follow the similar time course in a reversible manner. Therefore, further studies on the cellular mechanism for the plasticity of dendrites architecture might provide new insight into the etiological factors for stress-related mental illness such as posttraumatic stress disorder (PTSD).
In the current study we present evidence suggesting that PARP-1 regulates neurogenesis and its deficiency may result in schizophrenia-like behavioral deficits in mice. PARP-1 knockout neural stem cells exhibited a marked upregulation of embryonic stem cell phosphatase that can suppress the proliferative signaling of PI3K-Akt and ERK. The suppressed activity of Akt and ERK in the absence of PARP-1 results in the elevation of FOXO1 activity and its downstream target genes p21 and p27, leading to the inhibition of neural stem cell proliferation. Moreover, expression of neurogenic factors and neuronal differentiation were decreased in the PARP-1 knockout neural stem cells whereas glial differentiation was increased. In accordance with the in vitro data, PARP-1 knockout mice exhibited reduced brain weight with enlarged ventricle as well as decreased adult neurogenesis in the hippocampus. Interestingly, PARP-1 knockout mice exhibited schizophrenia-like symptoms such as anxiety, depression, social interaction deficits, cognitive impairments, and prepulse inhibition deficits. Taken together, our results suggest that PARP-1 regulates neurogenesis during development and in adult and its absence may lead to the schizophrenia-like behavioral abnormality in mice.
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